Although not very many reports have been made on a low-molecular-weight, non-peptide type compound having antagonistic activity against both substance P receptors (NK1 receptors) and neurokinin A receptors (NK2 receptors), for example, the below-described compounds A, B and C are known as such compounds. According to the specification of PCT publication No. WO 94/17045, the compound B has antagonistic activity against both NK1 and NK2 receptors. A pharmacological test of the compound B made by the present inventors, however, has revealed that the antagonistic activity of the compound B against NK1 receptors in vitro was markedly weak. In addition, when all of these compounds are orally administered, these are accompanied by problems such as insufficient antagonistic activity against both NK1 receptors and NK2 receptors. 
For a long time, the present inventors have carried out an extensive investigation on the synthesis of derivatives having antagonistic activity against tachykinin (particularly, antagonism against substance P, antagonistic activity against neurokinins A and B) and their pharmacological activity. As a result, it has been found that compared with the above-described known compounds, specific novel salts of an optically active substance of spiro[benzo[c]thiophene-1(3H),4xe2x80x2-piperidin]-2-oxide having an absolute configuration of S exhibit better oral absorption and excellent antagonistic activity against both NK1 and NK2 receptors to complete the present invention.
An object of the present invention is to provide the above-described compound. Another object of the present invention is to provide a medicament comprising the above-described compound as an effective ingredient, particularly, as a preventive agent or remedy (a composition for prophylaxis or treatment) for tachykinin-mediated diseases. A further object of the present invention is to provide a use of the above-described compound for the preparation of a medicament, particularly, a preventive agent or remedy (a composition for the prevention or treatment) of tachykinin-mediated diseases or is to provide a method for preventing or treating tachykinin-mediated diseases, which comprises administering a pharmacologically effective amount of the compound to a warm-blooded animal.
Examples of the preventive agent or remedy include inhibitors of an NK1 receptor and/or NK2 receptor. Examples of the diseases include diseases of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative diseases such as dementia of AIDS, Alzheimer""s senile dementia, Alzheimer""s disease, Down""s syndrome, demyelinating disease, amyotrophic lateral sclerosis, neuropathy, peripheral neuropathy and neuralgia; respiratory diseases such as chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchoconstriction, asthma and cough; inflammatory diseases such as inflammatory bowel disease (IBD), psoriasis, fibrosis, arthrosteitis, degenerative arthritis and rheumatoid arthritis; eczema; allergies such as rhinitis; hypersensitivity diseases such as hypersensitivity to vines; ophthalmological diseases such as conjunctivitis, vernal conjunctivitis, vernal catarrh, destruction of the blood-aqueous humor barrier caused by various inflammatory eye diseases, elevated introcular pressure and miosis; skin diseases such as contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; addictions such as alcohol dependency; somatic diseases caused by stress; sympathetic reflex dystrophy such as hand and shoulder syndrome; dysthymia; undesirable immune reactions such as rejection of grafts; diseases relating to immunopotentiation such as systemic lupus erythematosus or immunosuppression; digestive diseases such as diseases caused by abnormalities in nerves regulating the organs, colitis, ulcerative colitis and Crohn""s disease; emesis such as emesis induced by adverse effects of X-ray irradiation and chemotherapy, poisons, toxins, pregnancy, vestibular disorders, postoperative illness, gastrointestinal occlusion, reduced gastrointestinal movement, visceral pain, migraine headache, increased intracranial pressure, reduced intracranial pressure or adverse reaction induced by administration of various medicaments; urinary bladder functional diseases such as cystitis and urinary incontinence; eosinophilia caused by collagen diseases, scleriasis or Fasciola hepatica infection; diseases caused by abnormal blood flow due to vasodilation or vasoconstriction such as angina pectoris, migraine headache and Reynauds""s disease; and pain of pain nociceptive reception such as migraine headache, headache and toothache.
The novel salts of an optically active sulfoxide derivative according to the present invention are the hydrochloride and fumarate of 1-{2-[(2R)-(3,4 -dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[benzo(c)thiophene-1(3H),4xe2x80x2-piperidin]-(2S)oxide.
A novel medicament according to the present invention comprises a compound selected from the above-described ones as an active ingredient;
a novel preventive agent or remedy for tachykinin-mediated diseases according to the present invention comprises a compound selected from the above-described ones as an active ingredient,
a novel inhibitor of an NK1 receptor and/or an NK2 receptor according to the present invention comprises a compound selected from the above-described ones as an active ingredient,
a novel preventive agent or remedy for asthma and/or bronchitis according to the present invention comprises a compound selected from the above-described ones as an active ingredient,
a novel preventive agent or remedy for rhinitis according to the present invention comprises a compound selected from the above-described ones as an active ingredient,
a novel preventive agent or remedy for allergy according to the present invention comprises a compound selected from the above-described ones as an active ingredient, and
a novel preventive agent or remedy for urinary incontinence according to the present invention comprises a compound selected from the above-described ones as an active ingredient.
Use for the preparation of a medicament according to the present invention comprises using a compound selected from the above-described ones,
use for the preparation of a preventive agent or remedy for tachykinin-mediated diseases according to the present invention comprises using a compound selected from the above-described ones,
use for the preparation of an inhibitor of an NK1 receptor and/or an NK2 receptor according to the present invention comprises using a compound selected from the above-described ones,
use for the preparation of a preventive agent or remedy for asthma and/or bronchitis according to the present invention comprises using a compound selected from the above-described ones,
use for the preparation of a preventive agent or remedy for rhinitis according to the present invention comprises using a compound selected from the above-described ones,
use for the preparation of a preventive agent or remedy for allergy according to the present invention comprises using a compound selected from the above-described ones, and
use for the preparation of a preventive agent or remedy for urinary incontinence according to the present invention comprises using a compound selected from the above-described ones.
In the salts of an optically active sulfoxide derivative according to the present invention, 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[benzo(c)thiophene-1(3H),4xe2x80x2-piperidin]-(2S)oxide is a compound represented by the following structural formula (I): 
(wherein,  greater than S*xe2x86x92O represents a sulfoxide group wherein the oxygen atom is attached to the sulfur atom in the S absolute configuration).
Of the hydrochloride and fumarate of 1-{2-[(2R)-(3,4-dicholorophenyl)-4-(3,4, 5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[benzo(c)thiophene-1(3H),4xe2x80x2-piperidin]-(2S)-oxide according to the present invention, the hydrochloride is the more preferred.
xe2x80x9cThe hydrochloride and fumarate of 1-{2-[(2R)-(3,4-dichlorophenyl)4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[benzo(c)thiophene-1(3H),4xe2x80x2-piperidin]-(2S)-oxidexe2x80x9d according to the present invention happen to be solvates, absorbing water or a recrystallization solvent when they are allowed to stand in the air or are recrystallized. Such salts are also embraced in the present invention.
The salts of an optically active sulfoxide derivative according to the present invention can be prepared by converting xe2x80x9c1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl}spiro[benzo(c)thiophene-1(3H),4xe2x80x2-piperidin]-(2S)-oxidexe2x80x9d obtained in accordance with Referential Examples, described below, into its hydrochloride or fumarate in a known manner.
The novel salts of an optically active sulfoxide derivative according to the present invention exhibit excellent antagonistic action against both substance P receptors and neurokinin A receptors and besides, they have low toxicity so that they are useful as a preventive agent or remedy for tachykinin-mediated diseases. Examples of such diseases are diseases of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative diseases such as dementia of AIDS, Alzheimer""s senile dementia, Alzheimer""s disease, Down""s syndrome, demyelinating disease, amyotrophic lateral sclerosis, neuropathy, peripheral neuropathy and neuralgia; respiratory diseases such as chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchoconstriction, asthma and cough; inflammatory diseases such as inflammatory bowel disease (IBD), psoriasis, fibrosis, arthrosteitis, degenerative arthritis and rheumatoid arthritis; eczema; allergies such as rhinitis; hypersensitivity diseases such as hypersensitivity to vines; ophthalmological diseases such as conjunctivitis, vernal conjunctivitis, vernal catarrh, destruction of the blood-aqueous humor barrier caused by various inflammatory eye diseases, elevated introcular pressure and miosis; skin diseases such as contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; addictions such as alcohol dependency; somatic diseases caused by stress; sympathetic reflex dystrophy such as hand and shoulder syndrome; dysthymia; undesirable immune reactions such as rejection of grafts; diseases relating to immunopotentiation such as systemic lupus erythematosus or immunosuppression; digestive diseases such as diseases caused by abnormalities in nerves regulating the organs, colitis, ulcerative colitis and Crohn""s disease; emesis such as emesis induced by adverse effects of X-ray irradiation and chemotherapy, poisons, toxins, pregnancy, vestibular disorders, postoperative illness, gastrointestinal occlusion, reduced gastrointestinal movement, visceral pain, migraine headache, increased intracranial pressure, reduced intracranial pressure or adverse reaction induced by administration of various medicaments; urinary bladder functional diseases such as cystitis and urinary incontinence; eosinophilia caused by collagen diseases, scleriasis or Fasciola hepatica infection; diseases caused by abnormal blood flow due to vasodilation or vasoconstriction such as angina pectoris, migraine headache and Reynauds""s disease; and pain of pain nociceptive reception such as migraine headache, headache and toothache.
Examples of the administration route of the salts of an optically-active sulfoxide derivative according to the present invention include oral administration by, for example, tablets, capsules, granules, powders or syrups, and parenteral administration by injection, suppository or the like. Such pharmaceutical preparations can be prepared by methods well known in the art by using additives such as excipients (examples include organic excipients such as sugar derivatives, e.g., lactose, sucrose, dextrose, mannitol and sorbitol; starch derivatives, e.g., corn starch, potato starch, a-starch, dextrin and carboxymethyl starch; cellulose derivatives, e.g., crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium and internally cross-linked carboxymethylcellulose sodium; gum arabic; dextran; and pullulan; and inorganic excipients such as silicate derivatives, e.g., light anhydrous silicic acid, synthetic aluminum silicate and magnesium aluminate metasilicate; phosphates, e.g., calcium phosphate; carbonates, e.g., calcium carbonate; and sulfates, e.g., calcium sulfate), lubricants (examples include stearic acid; metal salts of stearic acid such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as bee gum and spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; sodium salts of aliphatic acids; laurylsulfates such as sodium laurylsulfate and magnesium laurylsulfate; silicic acids such as anhydrous silicic acid and silicate hydrate; and the above-described starch derivatives), binders (examples include polyvinyl pyrrolidone, macrogol and compounds similar to the above-exemplified excipients), disintegrators (examples include compounds similar to the above-exemplified excipients and chemically modified starches and celluloses such as crosscarmellose sodium, carboxymethyl starch sodium and crosslinked polyvinylpyrrolidone), stabilizers (examples include paraoxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenol and phenol derivatives such as cresol; thimerosal; dehydroacetic acid; and sorbic acid), corrigents (examples include ordinarily-employed sweetening agents, sour agents and perfumes) and/or diluents.
The dose of the compound of the invention will vary depending on the condition and age of the patient, administration route, and the like. The compound is orally administered in an amount of from 0.01 mg/kg weight (preferably 0.1 mg/kg weight, lower limit) to 100 mg/kg weight (preferably 50 mg/kg weight, upper limit) in a single dose; on the other hand, the compound is intravenously administered in an amount of 0.01 mg/kg weight (preferably 0.05 mg/kg weight, lower limit) to 100 mg/kg weight (preferably 50 mg/kg weight, upper limit) in a single dose. It is desired to administer the compound from once to several times a day depending on the condition of the patient, i.e., human or other mammal.